1 BACKGROUND

Young-onset type 2 diabetes (YT2D) is characterized by poorer glycaemic control, a higher complications burden and premature mortality when compared with older-onset T2D.1-3 It is now recognized that the more rapid and progressive decline in β-cell function seen in YT2D contributes to this higher-risk clinical picture.4 Preservation of β-cell secretory function early in the disease course is now a central focus of research to improve outcomes in YT2D. Although early improvement of glucotoxicity has long been postulated to have beneficial effects on the β-cell,5 the promise of first-line insulin treatment has not been shown to be of benefit in YT2D.4 Interestingly, there is an increasing body of evidence suggesting that glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibitors may protect or even augment β-cell function.6-8 In addition, the clinical efficacy of early combination therapy in YT2D with respect to the improvement in durability of glycaemic control is increasingly being recognized.9, 10 Here we report key feasibility, glycaemic and β-cell secretory outcomes of a 12-month pilot study exploring a novel, continuous glucose monitor (CGM)-guided, rapid treatment intensification (RTI) strategy to achieve early stringent glycaemic control, with the stepped use of empagliflozin and add-on liraglutide in young adults with recently diagnosed T2D.

2 METHODS

A single centre, open-label, parallel group, pilot randomized trial involving 20 young adults (18-40 years) with a recent diagnosis of T2D was performed. All participants tested negative for GAD and IA-2 autoantibodies before enrolment. Diagnosis of diabetes was confirmed by a glycated haemoglobin (HbA1c) ≥6.5% (48 mmol/mol) or a diagnostic oral glucose tolerance test (OGTT). All participants commenced the study within 12 months of diagnosis. This study tested a stepped, CGM-guided, RTI strategy (utilizing metformin ± empagliflozin± liraglutide) to achieve early intensive glycaemic control over 6 weeks, against a standard of care (SOC) strategy based upon the 2016 Australian Diabetes Society T2D treatment guidelines with treatment intensification directed by 3-monthly HbA1c assessment.11 At the beginning of the study, in addition to the introduction of pharmacotherapy, as per study protocol, all participants attended a 1-h education session with a specialist dietitian to review contemporary dietary recommendations for patients with recently diagnosed T2D. A comprehensive overview of both treatment strategies is provided in Figure S1a,b (see Appendix S1).

Following recruitment, individuals were assigned (1:1) to RTI and SOC groups on the basis of minimization considering gender, age, HbA1c, estimated glomerular filtration rate, urine albumin-to-creatinine ratio and body mass index at baseline. The open-source MinimPy program,12 incorporating a random element, was used to facilitate the allocation process.

2.1 Assessment of early glycaemic control

For the RTI group, the blinded FreeStyle Libre Pro CGM system (Abbott Diabetes Care, Alameda, California, United States) was employed to guide treatment intensification and CGM recordings were reviewed on a weekly basis for the first 6-week RTI period. The target level for mean interstitial glucose was set at <7.56 mmol/L, corresponding to an HbA1c of <6.5%.13 If CGM data revealed a mean blood glucose level (BGL) ≥7.56 mmol/L for the final 48 h of a weekly period, treatment was intensified according to the treatment algorithm (Figure S2 in Appendix S1). Achievement of early glycaemic control was defined by ascertainment (and maintenance) of the target (mean) BGL during the initial 6-week period. Ongoing glycaemic monitoring involved quarterly assessment of HbA1c for all participants.

2.2 Assessment of the effect of treatment strategy on β-cell function

The Insulin Secretion-Sensitivity Index-2 (ISSI-2)14, 15 was selected as the surrogate marker of β-cell function for this study. OGTT was performed at baseline, 6 and 12 months, and testing was conducted after ≥1-week treatment washout for all participants at each time point. Measurements of insulin and glucose levels at 0, 30, 60 and 120 min during the OGTT were used to derive the ISSI-2 results. The proportions of participants recording a favourable change in ISSI-2 at 6 months and again at 12 months in the RTI and SOC treatment groups were determined.

2.3 Statistical methods

Participants were analysed in the treatment group to which they were allocated based on the intention-to-treat principle. Descriptive statistics were used to summarize baseline and on study clinical measures.

As a pilot, all efficacy outcomes were deemed exploratory. Nonetheless, differences in mean achieved HbA1c between intervention and control groups were compared using the independent samples t-test at each quarterly study visit. Within-group HbA1c differences at each quarterly visit (relative to baseline HbA1c) were compared using the paired samples t-test.

Given significant heterogeneity of ISSI-2 results at baseline, a decision was made to compare percentage change in ISSI-2 at 6 and 12 months using each individual’s baseline result as a reference point. Three participants recorded very low ISSI-2 results at baseline and these individuals went on to record very large percentage increases in ISSI-2 at 6 and 12 months. In this setting, the process of Winsorization was utilized to address the issue of significant outliers.

All statistical tests were two-tailed and conducted at the p <.05 significance level. All analyses were performed using SPSS (Version 26.0; IBM Corp. Armonk, NY, USA).

3 RESULTS

A CONSORT flow diagram for the study is included as Figure S3 in Appendix S1. In total, 20 of 24 eligible individuals chose to enrol in the study; 10 of 11 RTI group and eight of nine SOC group participants completed the pilot. Baseline characteristics of the multi-ethnic study population are presented in Table S1 (in Appendix S1). The mean age of all participants was 29.9 ± 5.9 years and 75% were men. Baseline HbA1c (8.8% vs. 8.9%) and mean time since diagnosis (3.8 vs. 3.4 months) were similar for the RTI and SOC groups.

3.1 Safety and achievement of early stringent glycaemic control

The CGM-guided, RTI strategy was successful in achieving early stringent glycaemic targets as evidenced by the following: nine of 10 achieved the target average BGL (<7.56 mmol/L) by the end of the initial 6-week RTI period; median CGM-derived average BGL was significantly lower at the end of week 6 than week 1 (6.2 vs. 9.7 mmol/L, p = .03); median time in range (3.9-10.0 mmol/L) increased from 60% to 96% (week 1 vs. week 6, p = .02). Improvement in average BGL was achieved without any clinically significant hypoglycaemia or serious adverse events.

Early requirement for pharmacotherapy varied significantly within the RTI group. At the end of the initial, 6-week RTI period, one participant had been intolerant to metformin and maintained adequate glycaemic control utilizing dietary control alone. Of the remaining RTI group participants, one was receiving treatment with metformin monotherapy and one with empagliflozin monotherapy; four participants were receiving dual therapy (metformin and empagliflozin) and three participants were receiving triple therapy (metformin, empagliflozin and liraglutide).

3.2 Durability of glycaemic control and need for treatment intensification

Of the nine RTI group participants who achieved the target BGL at the end of week 6, seven recorded an HbA1c <6.5% at their 6-month study visit. Quarterly HbA1c data for the RTI and SOC groups are presented in Figure 1A.

A, Mean quarterly glycated haemoglobin (HbA1c) results for rapid treatment intensification (RTI) and standard of care (SOC) groups. B, Comparative requirement for treatment intensification within the RTI and SOC groups. C, Distribution of pharmacotheraphy utilization at various study time points for the RTI group. D, Distribution of pharmacotheraphy utilization at various study time points for the SOC group

With equivalent baseline HbA1c measures, Figure 1A shows that good glycaemic control was achieved by both the RTI and the SOC groups. As a pilot, this study was not powered to test superiority of RTI over SOC, although we note that the point estimate for mean HbA1c was lowest for the RTI group at each quarterly assessment.

Treatment regimens utilized by study participants in the RTI and SOC groups at study end are summarized in Table S2A (in Appendix  S1 ). Once established on a treatment regimen during the RTI period, greater durability of stringent glycaemic control was achieved; none of the RTI group participants required further treatment intensification for 6 months and 67% of RTI participants maintained satisfactory glycaemic control without need for further treatment intensification (Figure 1B,C). A comparison of individual treatment regimens for the RTI group at the end of the 6-week RTI period and at the end of the study is presented in Table S2B (in Appendix  S1 ). In contrast, 63% of the SOC group required one or more adjustments to pharmacotherapy throughout the study period (Table S2C in Appendix  S1); 30%-50% of participants required treatment intensification at each quarterly assessment (Figure 1B,D). Interestingly, while more patients in the RTI group were on multiple agents at 3 months, by study end more than 50% of the participants in the RTI group were only on mono- or dual therapy. In contrast, the treatment burden was greater in the SOC group where nearly 40% were requiring quadruple therapy for glucose control at 12 months.

3.3 β-cell function

An overview of absolute ISSI-2 results at baseline, 6 and 12 months for the RTI and SOC groups is presented in Table S3 (in Appendix  S1 ). Figure 2 illustrates percentage changes in ISSI-2 at 6 and 12 months relative to baseline for both treatment groups. Nine of 10 (90%) RTI participants versus six of eight (75%) SOC participants recorded an improvement in ISSI-2 at 6 months relative to baseline. At 12 months, four of nine (44%) of the RTI participants versus two of six (33%) of the SOC participants maintained their ISSI-2 improvement.

Winsorized percentage change in ISSI-2 (relative to baseline) for the rapid treatment intensification (RTI) (blue) and standard of care (SOC) (red) groups at 6 and 12 months

4 CONCLUSIONS

Here we present evidence that an individualized, CGM-guided, RTI strategy involving the stepped introduction of metformin ± empagliflozin ± liraglutide over 6 weeks is feasible, acceptable, safe and efficacious in achieving rapid early glycaemic control in young adults with recent-onset T2D. In total, 90% of RTI participants reached stringent glycaemic targets by 6 weeks and we observed significant heterogeneity in the pharmacotherapy required to achieve early glycaemic control.

These data also provide proof-of-concept evidence that the RTI strategy may allow for a high durability of excellent glycaemic control, with a reduced need to intensify therapy after the RTI period and a lower treatment burden by 12 months compared with usual care. Furthermore, in the process of analysing β-cell secretory function in the context of prevailing insulin sensitivity, we observed a higher proportion of the RTI group participants record an improvement in ISSI-2 after 6 and 12 months in the study. Taken together, these findings suggest that timely resolution of hyperglycaemia (utilizing metformin ± sodium-glucose cotransporter 2 inhibitors ± glucagon-like peptide-1 receptor agonists as required) in recently diagnosed T2D may lead to sustainable improvement in β-cell function. Evidently, given the small number of participants, further study will be required to confirm such a hypothesis.

Our results are in keeping with a Chinese study of early intensive insulin therapy in which the benefit of rapid ascertainment of good glycaemic control was shown with durable glycaemic response observed up to a year post-withdrawal of therapy.5 Rapidity with which good glycaemic response is achieved appears to be essential to β-cell response; the RISE studies highlighted that neither early insulin treatment in youth followed by metformin nor early use of liraglutide and metformin alone in adults attenuated progressive functional β-cell decline.4, 16

Clearly, greater durability of glycaemic benefit and persistence of functional β-cell improvement needs to be definitively proven before any new treatment paradigm is established. The findings of this pilot suggest a larger, even longer duration of randomized controlled trial of RTI is feasible and should be seriously considered to personalize evidence-based therapy in this challenging patient cohort.

ACKNOWLEDGMENTS

This study was approved by the Sydney Local Health District Ethics Review Committee (X16-0339) and was registered with the Australian Clinical Trials Registry (ACTRN12617000480381). The study was supported by funding from the RPAH Diabetes Centre Research Trust. TLM was supported by an Australian Postgraduate Research Scholarship. Elements of this study were presented in abstract form at the virtual Australasian Diabetes Congress, 11-13 November 2020.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

AUTHOR CONTRIBUTIONS

Timothy L. Middleton was involved in study design, data acquisition, analysis and interpretation and drafting of the manuscript. Maria I. Constantino and Margaret McGill assisted in the acquisition of data and provided critical review of the manuscript. Mario D'Souza contributed to the statistical analysis and critical review of the manuscript. Dennis K. Yue, Stephen M. Twigg, Ted Wu and Jencia Wong were involved in study design, contributed to data analysis and interpretation and provided critical review of the manuscript. The authors would like to thank Dr Eddy Tabet for acting as the independent endocrinologist guiding management of the SOC group. All authors approved the final manuscript for submission. Timothy L. Middleton is the guarantor of this work and, as such, had access to all study data and takes responsibility for data integrity and accuracy of the analyses.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Appendix S1. Supporting Information.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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